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On June 4, AFFiRiS AG offered a smattering of results from its Phase 2 clinical trial of AD02, an active vaccine for Alzheimer’s disease derived from the company’s proprietary method of making synthetic antigens based on the Aβ peptide. At a press conference in Vienna, company scientists reported that among older people with early Alzheimer’s, a placebo group fared better than any other. Patients in this group reportedly had less cognitive decline over the course of 18 months, correlating with less hippocampal shrinkage. This group had been injected not with any Aβ-based antigen, but only with what the company calls an immunomodulator that was part of the AD02 formulation. Company scientists then renamed this placebo formulation AD04, and said they planned to explore options for clinical development. The therapeutic that was the object of the trial, AD02, did not work.

“We believe what we are reporting is nothing less than a breakthrough in Alzheimer’s disease therapy,” CEO and company co-founder Walter Schmidt told reporters. Several AD clinical trial researchers contacted by Alzforum were unsure what to make of this announcement. They questioned the strength of the data disclosed thus far, and urged caution unless a clear rationale for AD04 emerges.

Schmidt declined to disclose the immunomodulator’s identity but said it has been used before in different indications. “This result came as a surprise,” he said at the press conference. “We assume the immune system is being activated, but we don’t know how.”

For the Phase 2 trial of AD02, AFFiRiS enrolled 332 men and women aged 50 to 80 from 40 centers around Europe. All had early AD. In the double-blind study, three groups of patients, about 70 in each, received four monthly injections of a low or a high dose of AD02 peptide antigen, delivered in two different formulations, followed by two booster shots at nine and 15 months. Two more groups of about 50 patients each received the same number of injections of two different forms of placebo, both containing a version of the undisclosed immunomodulator that was part of the AD02 formulations. (Vaccines are typically administered with adjuvants to boost the immune response to the antigen.) Schmidt said that the two placebo formulations, which are opaque, were necessary to keep the trial blinded.

Unexpectedly, nearly half the patients in the second placebo group appeared to be protected from cognitive decline and hippocampal atrophy, the company scientists said. According to Schmidt, this outcome constituted evidence of disease modification. Researchers contacted by Alzforum noted that the correlations between hippocampal atrophy and cognition in this trial occur in the absence of treatment, and that the data hence imply no treatment effect, per se.

For the primary endpoint shown at the press conference, the researchers combined the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS–Cog) and Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL) into a composite score. Typically in AD clinical trials, these batteries are analyzed and reported separately. In addition, AFFiRiS reported that some patients in this placebo group showed stable neurobehavioral patterns as determined by the Neuropsychiatric Inventory, and that caregiver quality of life was better than in the four other groups.

Outside experts were perplexed by the findings. Some pointed out that the company presented little actual data, such as sample sizes, standard errors, or dropout/completion numbers. "There is no reason why companies can't fully present their study design and protocol-specified outcomes in press conferences like this, so that outcomes can be fairly assessed,” Lon Schneider, University of Southern California, Los Angeles, wrote to Alzforum in an email. Most commentators declined to speak on the record.

Other researchers noted that if AD04 is indeed a therapeutic, then the AD02 groups should have performed as well, if not better, because AD02 contained AD04 plus the Aβ-based antigen. Could it be that AD02 counters AD04’s beneficial effects? Schmidt told Alzforum his group wondered the same thing but is unsure.

Some scientists suggested that the smaller patient numbers in the placebo groups versus the treatment groups could skew the results. Researchers commonly find that a significant number of AD patients do not progress during the time of trial observation, especially in early stages of the disease. In part because each trial features some non-progressors, the percent not progressing is not a commonly used way to show study results. It is more typical to show numeric decline on each outcome.

What about AD02 itself? This vaccine comprises a six-amino-acid affitope of Aβ’s N-terminus, meaning it mimics the primary amino acid structure of Aβ. According to AFFiRiS, the peptide fragment encourages B-cell recognition of Aβ while leaving the amyloid precursor protein alone and avoiding a pro-inflammatory T-cell response. Phase 1 data hinted that patients in the earliest stages of AD who took AD02 mounted a mild immune response and stopped declining on the Mini Mental State Examination (see Jun 2012 conference story). In the Phase 2 trial, patients on AD02 showed no statistically significant improvement over those in either placebo arm, though the safety monitoring board found all interventions to be safe and tolerable.

Patients from this study have been invited to participate in an open-label follow-up Phase 2 trial, though at the press conference, Schmidt said that the company was still deciding whether to continue that follow-up study. AFFiRiS plans to develop AD04 further, and perhaps AD02, but Schmidt said he and colleagues were still discussing how to move forward. In the future, the company would need to test AD04 against its own placebo and explore the optimum dose and injection frequency, he said.

A prior licensing agreement for AD02 has been terminated, Schmidt disclosed during the question period of the press conference. In 2008, GlaxoSmithKline had acquired rights to two AFFiRiS vaccines, according to Reuters. Click here to view the June 4 press conference. —Gwyneth Dickey Zakaib